RNF2 restricts African swine fever virus replication by promoting degradation of pA104R at lysine 5, with the K5R mutation increasing viral virulence and replication.
The host E3 ligase RNF2 restricts African swine fever virus replication by degrading the viral pA104R protein, a process that can be evaded by a viral K5R mutation leading to increased pathogenicity.
Absolute Event Rate: 0% vs 0%
The African swine fever virus (ASFV) -encoded late structural protein pA104R is a putative histone-like protein, which is also a DNA-binding related protein required for ASFV DNA replication, transcription, and genome packaging. However, the molecular mechanism underlying pA104R-host protein interactions remain unknown. To identify proteins potentially interacting with ASFV-pA104R, a primary porcine alveolar macrophage (PAM) cDNA yeast two-hybrid library was constructed, and the pig E3 ubiquitin ligase RING-finger protein 2 (RNF2) was identified, which specifically negatively regulates the proliferation of ASFV. Mechanistically, RNF2 inhibits ASFV replication by promoting the proteasomal degradation of ASFV-pA104R through K48-linked ubiquitination at pA104R lysine 5 (K5). Further studies showed that the K5R mutation impairs the interaction between pA104R and RNF2 and antagonizes for pA104R degradation by RNF2. An ASFV mutant carrying a pA104R point mutation (ASFV CN/SC/2019 pA104R-K5R) was generated based on the ASFV CN/SC/2019 (wild-type) strain. Furthermore, our findings indicate that ASFV CN/SC/2019 pA104R-K5R enhances viral replication and virulence, potentially by increasing viral transcription and/or modulating the host immune response. Accordingly, compared with the parental strain, ASFV CN/SC/2019 pA104R-K5R was more pathogenic and severe lesions in swine. Collectively, our study identifies an intrinsic antiviral protein RNF2 that mediates ASFV CN/SC/2019 pA104R-K5 site ubiquitination emerges as a potential determinant of viral replication and pathogenicity.
Zhang et al. (Fri,) reported a other. RNF2 restricts African swine fever virus replication by promoting degradation of pA104R at lysine 5, with the K5R mutation increasing viral virulence and replication.